Combining targeted DNA repair inhibition and immune-oncology approaches for enhanced tumor control.

Targeted therapy and immunotherapy have revolutionized cancer treatment. However, the ability of cancer to evade the immune system remains a major barrier for effective treatment. Related to this, several targeted DNA-damage response inhibitors (DDRis) are being tested in the clinic and have been shown to potentiate anti-tumor immune responses. Seminal studies have shown that these agents are highly effective in a pan-cancer class of tumors with genetic defects in key DNA repair genes such as BRCA1/2, BRCA-related genes, ataxia telangiectasia mutated (ATM), and others. Here, we review the molecular consequences of targeted DDR inhibition, from tumor cell death to increased engagement of the anti-tumor immune response. Additionally, we discuss mechanistic and clinical rationale for pairing targeted DDRis with immunotherapy for enhanced tumor control. We also review biomarkers for patient selection and promising new immunotherapy approaches poised to form the foundation of next-generation DDRi and immunotherapy combinations.
Competing Interests: Declaration of interests Dr. C.M.G. serves as a consultant or in an advisory role for G1 Therapeutics, AstraZeneca, BeiGene, Bristol Myers Squibb, Jazz Pharmaceuticals, and MonteRosa and receives research funding from AstraZeneca. L.A.B. serves as a consultant or in an advisory role for Merck Sharp & Dohme Corp., Arrowhead Pharmaceuticals, Chugai Pharma, AstraZeneca, Genentech Inc., Abbvie, BeiGene, and Jazz Pharmaceuticals and receives research funding from AstraZeneca and Amgen.
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